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Osteoclast Apoptosis: The Role of Fas in Vivo and in Vitro

Departments of Pathology (X.W., M.A.M., X.F., J.M.M.) and Nutrition Science (T.R.N.), University of Alabama at Birmingham, Birmingham, Alabama 35294; and Veterans Administration Medical Center (J.M.M.), Birmingham, Alabama 35233

Address all correspondence and requests for reprints to: Jay M. McDonald, Professor and Chair, Department of Pathology, Director, Center for Metabolic Bone Disease, University of Alabama at Birmingham, 509 Lyons Harrison Research Building, 1530 3rd Avenue South, Birmingham, Alabama 35294-0007. E-mail: mcdonald{at}path.uab.edu.

Both the number and the activity of osteoclasts are critical for maintaining normal bone turnover. The number is determined by rates of cell differentiation and death. Fas-mediated apoptosis is a dominant mechanism for apoptosis. Here, we show the presence of the Fas receptor on mouse, human, avian, and cultured RAW264.7 (murine) derived osteoclasts and the up-regulation of its expression during mouse osteoclast differentiation. Additionally, Fas is a fully functional death receptor in osteoclasts, and its signaling pathway is consistent with classical Fas signaling in other cell systems, involving mitochondrial release of cytochrome c and activation of caspases 3 and 9. This demonstration of Fas-mediated apoptosis in mature osteoclasts provides a new and potent mechanism for the regulation of osteoclast life span. The in vivo significance of Fas-mediated apoptosis in bone (osteoclasts) was demonstrated in aged Lpr and Gld mice, which have a dysfunctional immune system. Lpr mice, which have a defect in the Fas gene, have decreased bone mineral density, bone volume, trabecular thickness, and increased osteoclast number. Gld mice, which have a Fas ligand mutation, have a slight yet insignificant decrease in bone mineral density, but a highly significant increase in osteoclast number. Taken together, these data demonstrate that the Fas/Fas ligand system is important in the regulation of bone turnover and may represent a critical link between the immune system and bone remodeling in development and in various diseases.

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